The Milestones in Microbiology designation recognizes achievements of University of Texas at Dallas (UT-Dallas) scientists in molecular biology, in advancing medical science and in providing fundamental insights into bacteria, viruses and other microorganisms..

Milestones Site Dedication Ceremony

The plaque that marks the UT-Dallas Founders Building as a Milestones in Microbiology site was unveiled on November 10, 2016, in a ceremony held at the building. Susan Sharp, President of ASM, presented the Milestones plaque on behalf of ASM. Inga Musselman, Senior Vice Provost, UT-Dallas, accepted the plaque on behalf of the site.

Milestones Plaque

Historical Background and Perspective

Earliest History of the Site – In October 1964, the Founders Building was dedicated as the centerpiece of the Graduate Research Center of the Southwest (GRCSW), a private research institution, which in 1967, was renamed as the Southwest Center for Advanced Studies (SCAS), and then in 1969 became The University of Texas at Dallas (UT Dallas). As the first permanent structure on The University of Texas at Dallas campus, the Founders Building sits at the physical and historical heart of the University. In those early days, the building hosted faculty and visiting scholars from around the globe who conducted research and graduate education in mathematics, physics, geosciences, and atmospheric and space science. Biology, focusing on genetics and microbiology, was the largest division and the only molecular biology department in the Southwest at the time. Together those programs formed the core that would become UT-Dallas’ School of Natural Sciences and Mathematics.

The biology division included leaders in the field of microbiology, the study of organisms such as bacteria, viruses, fungi, protists and phages (viruses that infect bacteria). The first head of the Genetics Division was the phage biologist Carsten Bresch, who had been one of the first students of Max Delbrück, founder of the world-renowned Phage School. Among the earliest faculty recruits to the Genetics Division were Claud (Stan) Rupert, Hans Bremer, and Roy Clowes, whose accomplishments are highlighted below. A great deal of the early microbiology research done at UT Dallas was published in ASM journals.

Overview of Significance of Site – In its 50+ years, the Founders Building has welcomed some of the most distinguished scientists in the world, whose research – and that of their students and protégés – has advanced medical science and provided fundamental insights into the natural world, especially bacteria, viruses and other microorganisms. Biology (and microbiology in particular) has a rich history at UT Dallas and its predecessor institutions. Research conducted in this building has made major contributions to understanding the molecular genetics of bacteria and their viruses (bacteriophages). In overview, this designation honors the early developments of “molecular biology.”

Foundations of “Molecular Biology” – Early microbial genetics research at UT Dallas was integral to the development of the field of Molecular Biology. This “Molecular Biology” is firmly rooted in microbiology – the study of bacterial and phage genetics that prominently figures in the history of the Founders Building.

Regional Influence – Microbiologists working in the Founders Building were “pioneers,” introducing the new science of Molecular Biology to Texas and the Southwest region of the United States.

International Influence – From its very beginning, the Genetics Division of the GRSCW/SCAS was an international enterprise. The internationally-renowned Phage School and European scientists were influential on the early development of GRSCW/SCAS. Numerous trainees (PhDs and post-docs) of the Genetics Division and its descendants went on to highly successful careers in academia or industry (examples: Ry Young, now Professor, Texas A&M University; John Ryals, President and CEO, Metabolon). Several of the early faculty went on to continue distinguished careers in Europe and the US (example: Hermann Bujard left a faculty position at SCAS to join Heidelberg University. He later helped to establish the European Molecular Biology Organization (EMBO) and the Centre for Molecular Biology at Heidelberg University). Thus, GRSCW/SCAS has had a tremendous influence on the development of molecular biology in the US and worldwide.

Influence on Other Disciplines – Research activity in the department in other areas (cancer biology, neurobiology, biochemistry, cell biology) is to a large extent built upon the methodological foundations that were established by the early microbial geneticists.

Educational Mission – The Division of Genetics of the GRCSW Molecular Sciences Laboratory was the predecessor of the current Department of Biological Sciences. Microbiological research and teaching have long played a vital role in the mission of the Department.

Specific Accomplishments – Microbiologists at UT Dallas and its predecessor institutions used the bacterium Escherichia coli as a model organism to elucidate fundamental molecular biological principles concerning the repair, transfer and expression of DNA. In overview, the nomination encompasses the early developments of “molecular biology” – plasmids (Clowes), growth regulation (Bremer), and phage development including the highlight of the photoactivation of DNA repair (Rupert).

DNA Repair – Claud S. Rupert did seminal research on enzymes in bacteria that are activated by visible light and are involved with repairing damage to DNA caused by ultraviolet light; he was among the first to describe a light-activated DNA repair process that requires a photoreactivating enzyme, or photolyase. Rupert joined GRCSW from Johns Hopkins University, where he had discovered light-activated DNA repair. At GRCSW, Rupert continued to study photo-activation of DNA repair in Escherichia coli and other microorganisms. In 1978, Rupert and his student Aziz Sancar (Nobel Laureate, 2015, joint award) reported the cloning of the phr gene that encodes the E. coli photolyase. Sancar believes that phr was the first gene to be cloned (in a recombinant plasmid) anywhere in the US outside of California.

DNA Repair – Aziz Sancar (co-recipient 2015 Nobel Prize, 2015, for mechanistic studies of DNA repair), while a doctoral student at UT-Dallas in Rupert’s laboratory, successfully isolated the E. coli photolyase gene, which is critical to DNA repair in bacteria. Sancar earned his PhD in molecular and cell biology in 1977. His PhD research conducted in the Founders Building formed the foundation of subsequent work that led to his 2015 Nobel Prize (joint award) in chemistry. He is the first alumnus to earn the prize.

Plasmid Biology – Royston Clowes, an influential microbial geneticist who headed the biology division for several years, was internationally renowned for his research on the molecular biology of genetic elements (plasmids and transposons) that mediate DNA transfer. He did much to further understanding of the biology of plasmids and to lay the groundwork for their development as experimental tools. His work had implications for medicine and was at the center of recombinant DNA technology, which has had wide-ranging applications in biotechnology, laboratory research and drug development. His research was central to a better understanding of drug-resistance factors in disease-causing bacteria. Clowes’ "milestone" contributions in this area include the genetic and physical characterization of plasmids and studies of the mechanisms of plasmid and chromosome transfer. Together with other distinguished microbiologists (Naomi Datta, Stan Cohen, Stan Falkow, Roy Curtiss and Richard Novick), Clowes co-authored a definitive plasmid nomenclature and the “plasmid subgroup” report for the 1974 Asilomar meeting that formed the basis for the Guidelines for Recombinant DNA Research. Clowes also did important work on transposons and the exotoxin A of Pseudomonas aeruginosa, including one of the first reports of the isolation of DNA sequences encoding the toxin. Besides his research papers, Clowes also authored several important books, including the highly influential “Experiments in Molecular Genetics” (co-authored with Bill Hayes).

Bacterial Growth and the Synthesis of Macromolecules – Hans Bremer, associated with the institution for close to 50 years, uncovered fundamental physiological principles in bacterial growth and the synthesis of macromolecules. He made important contributions to the study of the growth rate regulation of ribosomal protein and RNA synthesis in Escherichia coli. "Milestone" contributions of Bremer’s include elucidation of the role of ppGpp in controlling the rate of stable RNA synthesis, the discovery that the second ppGpp synthetase activity of E. coli is the product of the spoT gene, and many studies of the growth rate regulation of macromolecular synthesis. Much of Bremer’s work is characterized by a strong quantitative and theoretical component, which reflects his roots in the Phage School. Still associated with UT-Dallas, Bremer’s publishing career with the institutions associated with the Founders Building spans nearly fifty years.

In ADDITION – Besides the individuals highlighted above, early members of GRCSW and SCAS included phage biologists and geneticists working on bacteria, yeast, Physarum, and protozoa.

The Milestones in Microbiology designation is made in recognition of Merck Research Laboratories’ strong and sustained legacy of anti-infective and vaccine research, and encompasses work accomplished in both the Rahway, NJ and West Point, PA facilities.

Milestones Site Dedication Ceremony

The plaques that will mark Merck Research Laboratories (MRL) as a Milestones in Microbiology site were unveiled on October 17, 2016, in a ceremony held in conjunction with the opening of Merck's 125th Anniversary celebration. Susan Sharp, President of ASM, presented the plaque on behalf of ASM. Roger Perlmutter, President of MRL, accepted the plaque on behalf of Merck.

The Milestones designation is for Merck Research Laboratories’ strong and sustained legacy of anti-infective and vaccine research, and recognizes accomplishments in both the Rahway, NJ and West Point, PA facilities.

RAHWAY FACILITY:

Pioneering Breakthroughs and Contributions – Since its opening in 1903, Merck’s Rahway facility has been the location for many therapeutic breakthroughs in the anti-infective space. Notably, scientists at Rahway conducted pioneering work in the development of

penicillin,

streptomycin,

Mefoxin® (cefoxitin),

Primaxin®(imipenem/cilastatin),

Mectizan® (ivermectin) and

Cancidas® (caspofungin acetate) g. as well as other life-saving products

New Way to Conduct Inquiry: Formal Collaboration Between Academia and Industry – Merck worked with Selman Waksman (Rutgers University, New Jersey) to secure one of the earliest formal collaborations between a business and a university. This early example of effective, cooperative academic and industrial collaboration is still touted today, and this partnership and later collaboration with Mayo Clinic allowed Merck scientists to show that streptomycin was the chemotherapeutic medicine found to be effective for tuberculosis.

Large Scale Production of Penicillin – While Merck cannot claim the discovery of penicillin, the company developed one of the first methods for its large scale production. Prior to Merck’s involvement, academic scientists were producing penicillin in static cultures on nutrient media. This process was laborious and yielded limited quantities of the active ingredient for therapeutic purposes. Merck scientists and engineers worked to scale up and enhance the penicillin yields from these cultures. Using pilot plants, they generated several hundred liters of penicillium culture that by March 1942 had yielded enough penicillin for the first patient, and another 10 cases were treated by June 1942. Further work involving Merck working in collaboration with other pharmaceutical companies and government agencies succeeded in advancing and refining a method of deep tank fermentation that increased yields substantially and ultimately paved the way for the mass production of penicillin.

Streptomycin – In 1939, Professor Selman A. Waksman of Rutgers University and George W. Merck, Merck ’s then CEO, secured one of the first ever formal collaborations between a business and a university to further explore the potential for isolating and characterizing antimicrobial agents derived from actinomycetes species found in soil samples. This agreement provided Waksman with support from Merck’s chemists and access to extensive animal testing resources, as well as state of the art pilot plant facilities. This early example of effective, cooperative academic and industrial collaboration is still touted today and this partnership and later collaboration with Mayo Clinic allowed Merck scientists to show that streptomycin was the first chemotherapeutic medicine found to be effective for tuberculosis.

Natural Products Screening Program – Following the success of the Waksman collaboration, Merck invested in a natural products screening program that ultimately led to the identification of several new antibiotic medicines. These capabilities, based mainly in Rahway, enabled Merck researchers to culture organisms sampled from sites all over the world which were then evaluated for antimicrobial activity. In the 1970s, following a fifteen-year effort, Merck’s screening procedure resulted in the discovery of Mefoxin® (cefoxitin). Mefoxin was an important new addition to the physician’s armamentarium due to the increasing incidence of antimicrobial resistance. Unlike cephalosporins that were originally discovered in fungi, Mefoxin® (cefoxitin) was interestingly derived from cephamycin C, which is produced by Streptomyces lactamdurans. At the time, it was recognized as a major advance over clinically available beta-lactam antibiotics.

Carbapenem Class Of Antibiotics – Primaxin® (imipenem/cilastatin) is the first member of the carbapenem class of antibiotics, which continues to be prescribed extensively in the U.S. and across the world. Carbapenems were an important discovery, as they are generally less susceptible to common mechanisms of antibiotic resistance than other beta-lactam molecules. The development of Primaxin® even today is considered one of the most arduous research efforts in Merck’s history to date. Screening of bacterial cultures identified a molecule, thienamycin, that had potent antibiotic properties. Unfortunately thienomycin was highly unstable. In 1974, the research teams at Rahway produced a sample pure enough to be chemically analyzed. This allowed the company’s chemists to develop and synthesize a stable derivative with similar antibiotic properties known as imipenem. Further experiments found that imipenem activity could be improved if it was administered with the dehydropeptidase inhibitor, cilastatin. The commercial manufacturing process for imipenem involved 16 defined steps at four locations, finishing in Rahway. The process was the first in Merck’s history and the most complex total chemical synthesis the industry had known.

River Blindness / Nobel Prize – Mectizan® (ivermectin): Research, performed predominantly in Rahway, led to the discovery and development of Mectizan® (ivermectin) for the treatment of onchocerciasis (also known as river blindness). River blindness is a parasitic infection by a parasitic worm Onchocerca volvulus that can cause intense itching, skin discoloration, rashes, and eye disease that can lead to permanent blindness. It is spread by the bites of infected black flies that breed in rapidly flowing rivers in the affected countries. The development of ivermectin coupled with Merck’s commitment to donate it worldwide (over 1 billion people treated to date), has led to the elimination of river blindness in several countries and significantly reduced the prevalence of this affliction worldwide by breaking the lifecycle of the causative parasite.

William C. Campbell, a retired Merck scientist who worked in Rahway, shared the 2015 Nobel Prize winner in Physiology or Medicine for the discovery of avermectin, which led to the development of Mectizan® (ivermectin).

Treatment for Fungal Infections – Cancidas® (caspofungin acetate): A 15-year process led Merck scientists to develop the first in class echinocandin antifungal agent, Cancidas® (caspofungin). Caspofungin is a semisynthetic derivative of pneumocandin B0, a naturally occurring molecule isolated from the fungus Glarea lozoyensis. Caspofungin is used today to treat opportunistic fungal infections of the genera Candida, Aspergillus, and Cryptococcus, particularly in patients who are immunocompromised. This medicine provided an important new option for patients, and by 2006, caspofungin had become the number one intravenous antifungal medicine worldwide.

WEST POINT FACILITY:

Vaccines – Merck’s West Point facility has been the location for pioneering work leading to the development of prophylactic vaccines for the protection of measles, mumps, rubella, hepatitis A, hepatitis B, pneumococcal disease and Human Papilloma Virus. In 1956, Maurice R. Hilleman became the director of virus and cell biology research at the Merck Institute, West Point, Pennsylvania. During his tenure, Hilleman and his team developed vaccines to prevent measles, mumps, hepatitis A, hepatitis B, meningitis, pneumonia, Haemophilus influenza bacteria and rubella. Notably, he cultivated mumps from a swab taken from his own daughter’s throat, using the culture as the basis of what became known as the Jeryl Lynn strain vaccine. Hilleman also succeeded in isolating and culturing other viruses, including the hepatitis A vaccine in culture. Additionally, Hilleman and his team developed a vaccine for hepatitis B by treating blood serum with pepsin, urea and formaldehyde; however, there were concerns about the purity of this vaccine during the HIV/AIDS epidemic. To address these concerns, Hilleman and his team developed an alternate hepatitis B vaccine using recombinant DNA technology. This was the first recombinant vaccine to be approved for widespread use. Today, Hilleman is recognized as one of the most influential contributors to modern day vaccinology.

Conveners: Joan W. Bennett; Rutgers, The State University of New Jersey

Lin-Jun MA; University of Massachusetts, Amherst

Symposium Description:

Every branch of the microbial sciences and clinical medicine has been transformed by our ability to exploit scientific insights into the molecular workings of life. This section will invite FIVE distinguished scientists who have made significant contributions to recent biology, including molecular cloning, DNA sequencing, and gene editing. Hearing stories from these scientists directly regarding why they chose their career paths, how they made their discoveries, and what they think about the economic, ethical and social implications of their research, will be extremely valuable for the next generation microbiologists.

Speakers/Topics:

The Ignition of BLAST

Stephen Altschul; NIH, Bethesda, MD

From the Lac Operon to Science and Social Justice Teaching

Jonathan Beckwith; Harvard University Medical School, Boston, MA

Microbial Genomics: The Early Years

Claire M. Fraser; University of Maryland, Baltimore, MD

Origins of Genomics and Semi-synthetic Genes

Joachim Messing; Rutgers, The State University of New Jersey, Piscataway, NJ

Following Carl Woese into the Natural Microbial World: The Beginnings of Metagenomics

Conveners: James A. Poupard; Chair, Center for the History of Microbiology/ASM Archives

Douglas E. Eveleigh; Rutgers, The State University of New Jersey

Lecture Description:

The 2016 History of Microbiology Lecture discusses the early work of Alexander Fleming on wound infections and what we would now call biofilm research. The history of bacteriology had been, in many ways, a history of the study of pure culture until significant research into the area of biofilms began in earnest in the 1990s. However, although the term “biofilm” did not appear in a publication until as late as 1977, the study of microbial communities attached to surfaces goes back to the earliest days of microbiology. Van Leeuwenhoek himself noted the abundance and diversity of microbes in dental plaque, while research in the 1940s by Heukelekian and Heller was among the first studies to note real differences between growth in a film and planktonic growth. Some of the earliest work on biofilms, particularly medically significant biofilms, was actually carried out by a young Alexander Fleming, long before his Nobel prize-winning work on penicillin. A review of the literature shows that Fleming authored or co-authored ten papers between 1914 and 1920 specifically on the mechanisms and treatment of infection. Among these papers are studies of the mixed flora found on soldiers’ uniforms and in different types of wounds and reports on innovative techniques that Fleming developed that allowed him to study biofilm populations. As a result of this work, Alexander Fleming was among the first to extensively characterize the diverse populations in biofilms and to recognize that organisms in a biofilm are often much more resistant to antimicrobial compounds than organisms growing planktonically. The Annual History of Microbiology Lecture is sponsored each year by the Center for the History of Microbiology/ASM Archives (CHOMA) to present topics in the history of microbiology and show how they have impacted and continue to influence the field of microbiology. The Lectures demonstrate that history is a critical factor for understanding the current and future directions of the science.